title: Smad6 inhibits non-canonical TGF-β1 signalling by recruiting the deubiquitinase A20 to TRAF6.
abstract: Transforming growth factor (TGF)-β, a pivotal cytokine involved in a variety of cellular functions, transmits signals through Smad-dependent canonical and Smad-independent noncanonical pathways. In contrast to the canonical TGF-β pathway, it is unknown how noncanonical TGF-β pathways are negatively regulated. Here we demonstrate that the inhibitory Smad Smad6, but not Smad7, negatively regulates TGF-β1-induced activation of the TRAF6-TAK1-p38 MAPK/JNK pathway, a noncanonical TGF-β pathway. TGF-β1-induced Smad6 abolishes K63-linked polyubiquitination of TRAF6 by recruiting the A20 deubiquitinating enzyme in AML-12 mouse liver cells and primary hepatocytes. In addition, the knockdown of Smad6 or A20 in an animal model or cell culture system maintains TAK1 and p38 MAPK/JNK phosphorylation and increases apoptosis, emphasizing the crucial role of the Smad6-A20 axis in negative regulation of the TGF-β1-TRAF6-TAK1-p38 MAPK/JNK pathway. Therefore, our findings provide insight into the molecular mechanisms underlying negative regulation of noncanonical TGF-β pathways.
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Su Myung
authors.initials: SM
authors.lastname: Jung
authors.forename: Ji-Hyung
authors.initials: JH
authors.lastname: Lee
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Park
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Oh
authors.forename: Sung Kyun
authors.initials: SK
authors.lastname: Lee
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Park
authors.forename: Youn Sook
authors.initials: YS
authors.lastname: Lee
authors.forename: Jun Hwan
authors.initials: JH
authors.lastname: Kim
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Yoe-Sik
authors.initials: YS
authors.lastname: Bae
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Seok Hee
authors.initials: SH
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000235:genetics*; D051905:Smad6 Protein / Q000235:genetics* / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D051905:Smad6 Protein; D048029:TNF Receptor-Associated Factor 6; D053773:Transforming Growth Factor beta1; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D044767:Ubiquitin-Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C497803:Smad6 protein, mouse; C513261:Tnfaip3 protein, mouse